tbuckley/cabot-search huggingface dataset:
Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial
Authors: Thomas Yau, Vittorina Zagonel, Armando Santoro, Mirelis Acosta-Rivera, Su Pin Choo, Ana Matilla, Aiwu Ruth He, Antonio Cubillo Gracian, Anthony B. El-Khoueiry, Bruno Sangro, Tarek E. Eldawy, Jordi Bruix, Giovanni Luca Frassineti, Gina M. Vaccaro, Marina Tschaika, Christian Scheffold, Petra Koopmans, Jaclyn Neely, Fabio Piscaglia
Journal: Journal of Clinical Oncology (2022)

To investigate the safety and efficacy of nivolumab plus cabozantinib with or without ipilimumab in patients with advanced hepatocellular carcinoma.In cohort 6 of the multicohort, open-label, phase I/II CheckMate 040 study, patients who were treatment-naive, sorafenib-intolerant, or had progressed on sorafenib were randomly assigned 1:1 to nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once daily (doublet arm); or nivolumab 3 mg/kg every 2 weeks plus cabozantinib 40 mg once daily with ipilimumab 1 mg/kg once every 6 weeks (triplet arm). Primary objectives were safety and tolerability, objective response rate, and duration of response by investigator assessment per RECIST v1.1. Secondary objectives included progression-free survival (by blinded independent central review) and overall survival.Seventy-one patients were randomly assigned: 36 to the doublet arm and 35 to the triplet arm. After 32.0-month median follow-up, objective response rate (95% CI) was 17% (6 to 33) and 29% (15 to 46) in the doublet and triplet arms, respectively. Median (95% CI) duration of response was 8.3 (6.9 to not estimable) months in the doublet arm and not reached (0.0 to not estimable) in the triplet arm. Median progression-free survival was 5.1 and 4.3 months, and median overall survival was 20.2 and 22.1 months for the doublet and triplet arms, respectively. Grade 3-4 treatment-related adverse events occurred in 50% and 74% of patients and treatment-related adverse events leading to discontinuation were reported for 11% and 23% in the doublet and triplet arms, respectively. There were no treatment-related deaths in either arm.Nivolumab plus cabozantinib with or without ipilimumab showed encouraging preliminary antitumor activity and had consistent safety profiles with those established for the individual drugs in patients with advanced hepatocellular carcinoma.
Mechanisms of current therapeutic strategies for heart failure: more questions than answers?
Authors: Muhammad Shahzeb Khan, Izza Shahid, Stephen J Greene, Robert J Mentz, Adam D DeVore, Javed Butler
Journal: Cardiovascular Research (2022)

Abstract Heart failure (HF) is a complex, multifactorial and heterogeneous syndrome with substantial mortality and morbidity. Over the last few decades, numerous attempts have been made to develop targeted therapies that may attenuate the known pathophysiological pathways responsible for causing the progression of HF. However, therapies developed with this objective have sometimes failed to show benefit. The pathophysiological construct of HF with numerous aetiologies suggests that interventions with broad mechanisms of action which simultaneously target more than one pathway maybe more effective in improving the outcomes of patients with HF. Indeed, current therapeutics with clinical benefits in HF have targeted a wider range of intermediate phenotypes. Despite extensive scientific breakthroughs in HF research recently, questions persist regarding the ideal therapeutic targets which may help achieve maximum benefit. In this review, we evaluate the mechanism of action of current therapeutic strategies, the pathophysiological pathways they target and highlight remaining knowledge gaps regarding the mode of action of these interventions.
ETS Fight Club on Microsatellite Enhancers
Authors: Thomas Mercher
Journal: Blood Cancer Discovery (2022)

Summary: In this issue of Blood Cancer Discovery, Kodgule, Goldman, Monovichet al. cleverly analyzed the transcription regulatory elements to investigate why the second copy of ETV6 is often lost in ETV6::RUNX1-translocated in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). It turns out that ETV6 suppresses the enhancer activity of GGAA microsatellite repeats, preventing ERG from subverting them to activate aberrant oncogene transcription. See related article by Kodgule, Goldman, Monovich et al., p. 34 (5).
Lower levels of small HDL particles associated with increased infectious disease morbidity and mortality: a population-based cohort study of 30 195 individuals
Authors: Mads Harsløf, Kasper M Pedersen, Shoaib Afzal, George Davey Smith, Børge G Nordestgaard
Journal: Cardiovascular Research (2022)

Low levels of HDL cholesterol have been associated with increased risk of infectious disease morbidity and mortality. Nuclear magnetic resonance (NMR) spectroscopy permits the measurement of HDL particle count and allows further subclassification according to particle size. We tested the hypothesis that low number of different HDL subfractions is associated with increased infectious disease morbidity and mortality.
Corrigendum to: Molecular biomarker-defined brain tumors: Epidemiology, validity, and completeness in the United States
Authors: J Bryan Iorgulescu, Chuxuan Sun, Corey Neff, Gino Cioffi, Catherine Gutierrez, Carol Kruchko, Jennifer Ruhl, Kristin Waite, Serban Negoita, Jim Hofferkamp, Tarik Tihan, Roger McLendon, Daniel J Brat, Quinn T Ostrom, Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2022)

In the
Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms
Authors: Lindsay M. Gurska, Rachel Okabe, Alexandra Schurer, Meng Maxine Tong, Mark Soto, Daniel Choi, Kristina Ames, Shira Glushakow-Smith, Allison Montoya, Ellen Tein, Linde A. Miles, Haiying Cheng, Pamela Hankey-Giblin, Ross L. Levine, Swati Goel, Balazs Halmos, Kira Gritsman
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAK/STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation. Experimental Design: Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/MET/RON/ROS1 inhibitor approved for the treatment of non–small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation. Results: We found that crizotinib suppresses proliferation and activation of JAK/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAK/STAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN. Conclusions: In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of patients with MPN.
Effectiveness of an Intervention to Improve Decision Making for Older Patients With Advanced Chronic Kidney Disease
Authors: Keren Ladin, Hocine Tighiouart, Olivia Bronzi, Susan Koch-Weser, John B. Wong, Sarah Levine, Arushi Agarwal, Lucy Ren, Jack Degnan, Lexi N. Sewall, Brianna Kuramitsu, Patrick Fox, Elisa J. Gordon, Tamara Isakova, Dena Rifkin, Ana Rossi, Daniel E. Weiner
Journal: Annals of Internal Medicine (2022)

Older patients with advanced chronic kidney disease (CKD) face difficult decisions about managing kidney failure, frequently experiencing decisional conflict, regret, and treatment misaligned with preferences.To assess whether a decision aid about kidney replacement therapy improved decisional quality compared with usual care.Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT03522740).8 outpatient nephrology clinics associated with 4 U.S. centers.English-fluent patients, 70 years and older with nondialysis CKD stages 4 to 5 recruited from 2018 to 2020.DART (Decision-Aid for Renal Therapy) is an interactive, web-based decision aid for older adults with CKD. Both groups received written education about treatments.Change in the decisional conflict scale (DCS) score from baseline to 3, 6, 12, and 18 months. Secondary outcomes included change in prognostic and treatment knowledge and change in uncertainty.Among 400 participants, 363 were randomly assigned: 180 to usual care, 183 to DART. Decisional quality improved with DART with mean DCS declining compared with control (mean difference, -8.5 [95% CI, -12.0 to -5.0]; P < 0.001), with similar findings at 6 months, attenuating thereafter. At 3 months, knowledge improved with DART versus usual care (mean difference, 7.2 [CI, 3.7 to 10.7]; P < 0.001); similar findings at 6 months were modestly attenuated at 18 months (mean difference, 5.9 [CI, 1.4 to 10.3]; P = 0.010). Treatment preferences changed from 58% "unsure" at baseline to 28%, 20%, 23%, and 14% at 3, 6, 12, and 18 months, respectively, with DART, versus 51% to 38%, 35%, 32%, and 18% with usual care.Latinx patients were underrepresented.DART improved decision quality and clarified treatment preferences among older adults with advanced CKD for 6 months after the DART intervention.Patient-Centered Outcomes Research Institute (PCORI).
Ultrafast prediction of somatic structural variations by filtering out reads matched to pan-genome k-mer sets
Authors: Jang-il Sohn, Min-Hak Choi, Dohun Yi, Vipin A. Menon, Yeon Jeong Kim, Junehawk Lee, Jung Woo Park, Sungkyu Kyung, Seung-Ho Shin, Byunggook Na, Je-Gun Joung, Young Seok Ju, Min Sun Yeom, Youngil Koh, Sung-Soo Yoon, Daehyun Baek, Tae-Min Kim, Jin-Wu Nam
Journal: Nature Biomedical Engineering (2022)
A transposable element into the human long noncoding RNA <i>CARMEN</i> is a switch for cardiac precursor cell specification
Authors: Isabelle Plaisance, Panagiotis Chouvardas, Yuliangzi Sun, Mohamed Nemir, Parisa Aghagolzadeh, Farhang Aminfar, Sophie Shen, Woo Jun Shim, Francesca Rochais, Rory Johnson, Nathan Palpant, Thierry Pedrazzini
Journal: Cardiovascular Research (2022)

Abstract Aims The major cardiac cell types composing the adult heart arise from common multipotent precursor cells. Cardiac lineage decisions are guided by extrinsic and cell-autonomous factors, including recently discovered long noncoding RNAs (lncRNAs). The human lncRNA CARMEN, which is known to dictate specification toward the cardiomyocyte (CM) and the smooth muscle cell (SMC) fates, generates a diversity of alternatively spliced isoforms. Methods and results The CARMEN locus can be manipulated to direct human primary cardiac precursor cells (CPCs) into specific cardiovascular fates. Investigating CARMEN isoform usage in differentiating CPCs represents therefore a unique opportunity to uncover isoform-specific functions in lncRNAs. Here, we identify one CARMEN isoform, CARMEN-201, to be crucial for SMC commitment. CARMEN-201 activity is encoded within an alternatively spliced exon containing a MIRc short interspersed nuclear element. This element binds the transcriptional repressor REST (RE1 Silencing Transcription Factor), targets it to cardiogenic loci, including ISL1, IRX1, IRX5, and SFRP1, and thereby blocks the CM gene program. In turn, genes regulating SMC differentiation are induced. Conclusions These data show how a critical physiological switch is wired by alternative splicing and functional transposable elements in a long noncoding RNA. They further demonstrated the crucial importance of the lncRNA isoform CARMEN-201 in SMC specification during heart development.
Risk and determinants of low and very low bone mineral density and fractures in a national cohort of Dutch adult childhood cancer survivors (DCCSS-LATER): a cross-sectional study
Authors: Jenneke E van Atteveld, Demi T C de Winter, Vincent G Pluimakers, Marta Fiocco, Rutger A J Nievelstein, Monique G G Hobbelink, Andrica C H de Vries, Jacqueline J Loonen, Eline van Dulmen-den Broeder, Helena J van der Pal, Saskia M F Pluijm, Leontien C M Kremer, Cécile M Ronckers, Margriet van der Heiden-van der Loo, A Birgitta Versluijs, Marloes Louwerens, Dorine Bresters, Hanneke M van Santen, Daniel S Olsson, Imo Hoefer, Sjoerd A A van den Berg, Jaap den Hartogh, Wim J E Tissing, Sebastian J C M M Neggers, Marry M van den Heuvel-Eibrink
Journal: The Lancet Diabetes & Endocrinology (2022)
Pharmacological advances in the treatment of nonalcoholic fatty liver diseases : focused on global results of randomized controlled trials
Authors: Jihyun An, Joo Hyun Sohn
Journal: Clinical and Molecular Hepatology (2022)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease globally, and its prevalence is rapidly increasing. Nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD, is characterized by hepatocellular injury, inflammation, and fibrosis. Patients with NASH or severe fibrosis should be treated according to international NAFLD guidelines. Currently, regulatory agencies have not approved any pharmaceutical treatment for NAFLD. Vitamin E and pioglitazone are efficacious for NASH resolution; however, their benefits must be weighed against the reported risks. In a phase 2 trial, a glucagon-like peptide-1 agonist commonly used for diabetes and obesity was found to improve liver histology in patients with NASH. Furthermore, therapeutic agents targeting NASH pathogenesis, including bile acid signaling, insulin resistance, and lipid metabolism, are in various phases of clinical development. In this article, we review the benefits and drawbacks of current pharmacotherapy and the efficacy of upcoming treatments for NASH.
Different phenotypes of drug‐induced anaphylaxis—Data from the European Anaphylaxis Registry
Authors: Theresa Hanschmann, Wojciech Francuzik, Sabine Dölle‐Bierke, Kathrin Scherer Hofmeier, Linus Grabenhenrich, Franziska Ruëff, Jean‐Marie Renaudin, Claudia Pföhler, Regina Treudler, M. Beatrice Bilò, Roland Lang, Luis Felipe Ensina, George Christoff, Victoria Cardona, Nicola Wagner, Norbert Reider, Sabine Müller, Heinrich Dickel, Margitta Worm
Journal: Allergy (2022)

Drugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment.Data from the European Anaphylaxis Registry (2007-2019) with 1815 reported cases of drug-induced anaphylaxis were studied accordingly.Drugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use.The study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines.
Challenging the Hemodynamic Hypothesis in Heart Failure With Preserved Ejection Fraction: Is Exercise Capacity Limited by Elevated Pulmonary Capillary Wedge Pressure?
Authors: Satyam Sarma, James P. MacNamara, Bryce N. Balmain, Christopher M. Hearon, Denis J. Wakeham, Andrew R. Tomlinson, Linda S. Hynan, Tony G. Babb, Benjamin D. Levine
Journal: Circulation (2022)

Background: Exercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF. Methods: Thirty patients with HFpEF (70±6 years of age; 63% female) underwent 2 bouts of upright, seated cycle exercise dosed with sublingual nitroglycerin or placebo control every 15 minutes in a single-blind, randomized, crossover design. PCWP (right heart catheterization), oxygen uptake (breath × breath gas exchange), and cardiac output (direct Fick) were assessed at rest, 20 Watts (W), and peak exercise during both placebo and nitroglycerin conditions. Results: PCWP increased from 8±4 to 35±9 mm Hg from rest to peak exercise with placebo. With nitroglycerin, there was a graded decrease in PCWP compared with placebo at rest (–1±2 mm Hg), 20W (–5±5 mm Hg), and peak exercise (–7±6 mm Hg; drug × exercise stage P =0.004). Nitroglycerin did not affect oxygen uptake at rest, 20W, or peak (placebo, 1.34±0.48 versus nitroglycerin, 1.32±0.46 L/min; drug × exercise P =0.984). Compared with placebo, nitroglycerin lowered stroke volume at rest (–8±13 mL) and 20W (–7±11 mL), but not peak exercise (0±10 mL). Conclusions: Sublingual nitroglycerin lowered PCWP during submaximal and maximal exercise. Despite reduction in PCWP, peak oxygen uptake was not changed. These results suggest that acute reductions in PCWP are insufficient to improve exercise capacity, and further argue that high PCWP during exercise is not by itself a limiting factor for exercise performance in patients with HFpEF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04068844.
Profound phenotypic and epigenetic heterogeneity of the HIV-1-infected CD4+ T cell reservoir
Authors: Vincent H. Wu, Jayme M. L. Nordin, Son Nguyen, Jaimy Joy, Felicity Mampe, Perla M. del Rio Estrada, Fernanda Torres-Ruiz, Mauricio González-Navarro, Yara Andrea Luna-Villalobos, Santiago Ávila-Ríos, Gustavo Reyes-Terán, Pablo Tebas, Luis J. Montaner, Katharine J. Bar, Laura A. Vella, Michael R. Betts
Journal: Nature Immunology (2022)

Abstract Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a considerable impediment in research towards a cure for HIV. To address this, we developed a single-cell strategy to precisely define the unperturbed peripheral blood HIV-infected memory CD4 + T cell reservoir from ART-treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by new and known surface markers within total and individual memory CD4 + T cell subsets. We further uncovered new epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that suggest infected cells with accessible provirus, irrespective of reservoir distribution, are poised for reactivation during ART treatment. Together, our findings reveal the extensive inter- and intrapersonal cellular heterogeneity of the HIV reservoir, and establish an initial multiomic atlas to develop targeted reservoir elimination strategies.
Increasing diversity in connectomics with the Chinese Human Connectome Project
Authors: Jianqiao Ge, Guoyuan Yang, Meizhen Han, Sizhong Zhou, Weiwei Men, Lang Qin, Bingjiang Lyu, Hai Li, Haobo Wang, Hengyi Rao, Zaixu Cui, Hesheng Liu, Xi-Nian Zuo, Jia-Hong Gao
Journal: Nature Neuroscience (2022)
Biology and therapeutic targeting of molecular mechanisms in MPNs
Authors: Joan How, Jacqueline S. Garcia, Ann Mullally
Journal: Blood (2022)

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription signaling. As a result, JAK inhibitors have been the standard therapy for treatment of patients with myelofibrosis (MF). Although currently approved JAK inhibitors successfully ameliorate MPN-related symptoms, they are not known to substantially alter the MF disease course. Similarly, in essential thrombocythemia and polycythemia vera, treatments are primarily aimed at reducing the risk of cardiovascular and thromboembolic complications, with a watchful waiting approach often used in patients who are considered to be at a lower risk for thrombosis. However, better understanding of MPN biology has led to the development of rationally designed therapies, with the goal of not only addressing disease complications but also potentially modifying disease course. We review the most recent data elucidating mechanisms of disease pathogenesis and highlight emerging therapies that target MPN on several biologic levels, including JAK2-mutant MPN stem cells, JAK and non-JAK signaling pathways, mutant calreticulin, and the inflammatory bone marrow microenvironment.